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1 Introduction

The evaluation of diagnostic agents is governed by the same regulatory rules and principles as those for other medicinal products. The requirements for applications for Marketing Authorization for medicinal products in the EU, including all contrast agents, are provided in Directive 2001/83/EC as amended.

Several guidance documents have been developed to further amplify the requests laid down in the legislation.

The most important guidelines which give advice on clinical evaluation are the following:

  • Guideline on Clinical Evaluation of Diagnostic Agents (EMEA 2010)

  • Good Clinical Practice (International Conference for Harmonization, ICH, topic E6)

  • Statistical Principles for Clinical Trials (ICH topic E9)

  • Choice of Control Group in Clinical Trials (ICH topic E10)

  • Structure and Content of Clinical Study Reports (ICH topic E3)

This chapter summarizes relevant sections of the Guideline on Clinical Evaluation of Diagnostic Agents (EMEA 2010), which outlines the principles for the clinical evaluation of diagnostic agents intended for in vivo administration. Further details specific for imaging agents, which concern classification, efficacy criteria, methodological issues, and safety assessments, are outlined in the appendix to this Guideline.

The European Public Assessment Reports for the two latest approved gadolinium-containing MR contrast agents, gadofosveset trisodium (Vasovist®—the name was changed to Ablavar® on January 10th 2011) and gadoversetamide (Optimark®) will be used to illustrate the non-clinical and clinical parts of the process of application for approval. On 18 October 2011, the European Commission issued a decision to withdraw the marketing authorization for Ablavar as requested by the Marketing Authorization Holder.

2 General Principles of Evaluation

The principles used for the evaluation of medicinal products with respect to quality, pharmacology, toxicology, pharmacokinetics, and safety also apply to diagnostic agents. However, since contrast agents are used to diagnose and monitor diseases or conditions and not for treatment, the clinical development programs have to be adapted accordingly. As for other medicinal products, the balance between benefits and risks should be taken into account when granting a marketing authorization.

In general, approval of a contrast agent is usually based on the clinical indications for its use rather than the general properties of a specific molecule. However, the general properties should be described in the application.

In practice, the requirements for authorization for completely new contrast agents may differ from those for contrast agents similar to contrast agents which have already been approved. Examples of the latter would be iodinated monomers or non-tissue-specific extracellular gadolinium chelates which share several similarities with an already approved contrast agent (such as chemical structure/class, pharmacokinetic profile, dose and dosing regimen of the active moiety), but frequently differ in the chemical structure of the carrier molecule. For such compounds, so-called non-inferiority comparative trials against a similar already approved agent are recommended. The aim is to show similar technical and diagnostic performances (sensitivity and specificity) as well as similar or better safety profile for the same patient population or indication. This relatively limited evidence for assessing the clinical benefit of these products is based on the claim(s) for the same indication which has already been granted to the similar approved contrast agent (the comparator). If the aim is to show superiority of the new contrast agent, this limited evidence may not be sufficient and, in addition to better technical and diagnostic performance, the impact on diagnostic thinking and patient management (see below) may need to be shown or at least discussed in the submission. However, if the impact of the diagnosis provided by the comparator contrast agent which has already been approved is widely accepted, better technical and diagnostic performance may be sufficient to support a claim of superiority.

If use for a new indication not approved for the similar contrast agent is claimed, the requirements for approval are identical to those required for a new product. It is then necessary to show adequate technical and diagnostic performance in relation to a standard of truth (for example, the histopathological diagnosis). In addition, when appropriate, technical and diagnostic performance should be compared to an established contrast agent in the clinical context in which the new agent is to be used.

3 Quality Aspects

Chemical, pharmaceutical, and biological aspects of the contrast agent should be presented in detail in the application.

A wide range of information about the active substance of the contrast agent should be provided, such as the composition and molecular structure and the administration form and dosage.

The stepwise manufacturing process should be adequately described, for example the chemical synthesis, purification steps, etc. Specifications for starting materials, reagents, catalysts, and solvents should be provided. Information on how the structure has been elucidated (e.g., elemental analysis, infrared spectroscopy, ultraviolet spectroscopy, optical rotation, mass spectrometry) should be given, together with data on how physico-chemical parameters (e.g., polymorphism, solubility, particle size) have been analyzed.

The active substance specification should include data on appearance, identification tests, purity control, and stability.

Also for the medicinal product the manufacturing process, product specification, and stability data should be provided.

4 Non-Clinical Evaluation

The non-clinical data comprises data on pharmacology, pharmacokinetics, and toxicology and studies should be performed in accordance with good laboratory practice requirements.

For example, when considering the pharmacological characteristics of magnetic resonance agents, the degree of albumin binding and the ability to alter proton relaxation times in vitro and in vivo are of the utmost importance. Depending on the claimed indication(s), other aspects such as renal contrast enhancement, imaging performance in cerebral metastatic disease, and permeability of the blood–brain barrier should be documented. Comparisons between contrast agents with similar structure may facilitate the evaluation. As an example, in vitro and in vivo investigations of primary as well as secondary pharmacodynamics were performed for the recently approved contrast agent gadoversetamide in comparison with gadopentetate dimeglumine.

In vitro and in vivo safety pharmacology studies should provide data on the effect on vital organ functions, such as convulsive threshold and risk of QT-prolongation.

Ideally, the potential for pharmacodynamic drug interactions should also be investigated. For example, for gadofosveset trisodium a series of drug interaction studies were performed to assess the ability to displace frequently used drugs, such as digoxin and warfarin, from their binding sites on human serum albumin. In addition, the potential effect of commonly used drugs on MRI efficacy was examined. For gadoversetamide, no studies on pharmacodynamic drug interactions were available before the marketing authorization was issued.

The pharmacokinetic data set should include data on absorption, biodistribution or bioavailability, metabolism, and excretion. The pharmacokinetic testing is typically performed in two or more of the species used for toxicology testing (rat, rabbit, dog, monkey) and using the administration route intended for use in man.

The toxicology test program should as a minimum include single dose toxicity, repeat dose toxicity, genotoxicity, carcinogenicity, and reproduction toxicity.

Finally potential ecotoxic and environmental risks should be assessed.

5 Clinical Evaluation

5.1 Good Clinical Practice (GCP) and Ethics

The clinical trials used to support the marketing authorization application should be designed, conducted, recorded, and reported in compliance with the GCP principles as laid down in regulations and guidelines. In addition, all studies should be conducted in accordance with the Declaration of Helsinki.

5.2 Fundamental Requirements

According to the guideline on clinical evaluation of diagnostic agents (EMEA 2010), in order to establish an indication for a contrast agent, it is necessary to demonstrate its benefit by assessing its technical performance (including procedural convenience), diagnostic performance, impact on diagnostic thinking, impact on patient management, impact on clinical outcome and safety. In addition, a clinical pharmacology study program should be performed to provide data on safety, tolerance, pharmacokinetics, and pharmacodynamic dose-related effects. EU and US requirements are very similar, but there are a few differences. For example, the FDA requirements do not include impact on diagnostic thinking, impact on patient management, and impact on clinical outcome.

It is necessary to assess technical performance, for example from image quality, but this on its own is not enough to show the clinical benefit of a new contrast agent and cannot be the sole basis for approval.

The diagnostic performance consists of the sensitivity and specificity of a test. The trade-off between sensitivity and specificity requires careful analysis in relation to the intended applications and the implications for patient care. The impact of disease prevalence should also be taken into consideration, as co-morbidity, specificity, and sensitivity may vary in different study populations.

The impact on diagnostic thinking refers to the impact of a test result on post-test versus pre-test probability of a correct diagnosis in a well-defined clinical context which includes patient characteristics and other diagnostic procedures. All diagnostic agents should have an impact on diagnostic thinking (higher probability of correct diagnosis after the test than before the test, or change in diagnosis). Positive as well as negative predictive values are important parameters which influence the impact on diagnostic thinking in a given patient. Both negative and positive predictive values depend on the prevalence of the disease in the studied series and may not necessarily reflect the prevalence of a disease in the overall population. The role of a diagnostic test in the determination of the prognosis may have significant impact on diagnostic thinking. Prognostic value should be demonstrated by adequate statistical methods such as multivariate analysis.

A description and quantification of the impact of the diagnostic information obtained on the management of a patient and of the clinical outcome are generally obtained through an appropriate questionnaire or by sequential unblinding. Patient follow-up data should be available for this purpose. Studies assessing patient outcomes may be required if there is no standard of truth to compare. In all other cases these studies are not mandatory, but, if performed, can be the basis for a specific claim. An assessment of the potential benefits and risks arising from the impact on therapeutic decisions should be made. In particular, the consequences of an incorrect diagnosis (false positive or false negative) must be considered.

For each claim the contrast agent may be used alone or in combination with other diagnostic procedures or medicinal products necessary for the indication claimed. This should always be specified in the study protocol. If several indications or claims are planned for one imaging agent it may be considered necessary to perform separate clinical trials.

5.3 Methodological Considerations

In the phase III studies the protocol should describe the trial objectives or claim, the contrast agents and methods investigated (including the investigational agent, absolute or surrogate standard of truth, comparator and other clinical assessments and procedures if used), testing procedures, trial population, sample size calculation, endpoint justification, blinding, randomization, statistical considerations, principles for data presentation, issues related to collection and analysis of data, safety and any other relevant considerations.

Relevant data on the diagnostic performance of the contrast agent obtained from earlier phases of its clinical development (phase II studies) should be used to design subsequent confirmatory trials.

Special attention should be given to the trade-off between sensitivity and specificity, taking the intended clinical use into consideration, and to the justification of power calculations and acceptance limits in relation to clinical relevance. It is particularly important to design the trials in relation to the intended clinical use of the contrast agent. For example, different trials will be required if the contrast agent under investigation will be used to provide additional information when insufficient diagnostic information is obtained from established tests or if it will be used as an alternative to established standard tests.

Comparative studies are required both if the investigational contrast agent is being developed as an alternative or as an improvement over existing contrast agents. An appropriate comparator agent would be one which is widely accepted in the EU for the claimed indication and reflects current good medical practice. The choice of comparator must be justified and the corresponding procedures clearly described. The comparison should include evaluation of both efficacy and safety data.

For contrast agents the unenhanced procedure may serve as an appropriate comparator for evaluating the added value of the contrast agent. However, comparison with a marketed comparator contrast agent is ideal.

Two previously submitted marketing authorization applications illustrate the process. For gadoversetamide (Optimark®), the four submitted pivotal studies shared the same design, and were multicenter, randomized, double-blind, non-inferiority studies to evaluate the safety, tolerance, and efficacy of gadoversetamide compared to gadopentetate dimeglumine in CNS or liver lesions. For gadofosveset trisodium (Vasovist®), no head-to-head comparisons with currently available MRA contrast agents were carried out because no extracellular agent had European-wide approval for MRA during the development of gadofosveset trisodium.

5.4 Strategy and Design of Clinical Trials

In phase I studies the aim is to obtain pharmacokinetic and first human safety data assessments with single mass dose and increasing mass doses of the diagnostic agent. Phase I trials may be done in healthy volunteers or in patients.

In phase II studies the aim is to determine the mass dose or dosing regimen in patients to be used in the phase III studies, and to provide preliminary evidence of efficacy and safety, as well as to optimize the technique and timing of, for example, image acquisition. In addition, phase II studies are important for developing methods or criteria by which images or test results can be evaluated.

For gadofosveset trisodium, seven clinical phase I/II pharmacological studies were performed in healthy volunteers, in patients with renal or hepatic impairment, or in patients with vascular disease. For gadoversetamide, five phase I and one phase II study were performed in healthy volunteers and patients with various CNS or liver pathologies, as well as a variety of renal and hepatic dysfunction.

Phase III studies are large-scale trials which aim to establish the efficacy of the contrast agent in a well-defined target patient population, and in the step of the diagnostic decision-making process, where the contrast agent will be used in later clinical practice. The primary efficacy variable should be clinically relevant and evaluable or measurable in all patients. Multiple primary endpoints should be avoided. When approval for multiple indications is requested, studies may be done in different clinical settings, each corresponding to the particular claim and intended use.

The clinical phase III study program for gadofosveset trisodium consisted mainly of four studies performed in different vascular territories, and enrolled from 136 to 268 patients in each study. The clinical phase III study program for gadoversetamide comprised two pivotal CNS studies and two pivotal liver studies, and enrolled from 198 up to 208 patients in each study.

5.5 Clinical Safety

A serious safety concern may prevent marketing authorization if there are alternative and safer diagnostic methods. Marketing authorization will always be based on the benefit/risk ratio of the new contrast agent. In some cases a contrast agent will have to show a positive impact on diagnostic thinking and patient management to support a marketing authorization claim.

Clinical safety assessments of contrast agents should be designed based on their characteristics and intended use(s) and on the results of other relevant clinical studies. Safety follow-up of patients should not be limited to the duration of the diagnostic procedure, but extended to a longer time period corresponding at least to the pharmacokinetic and pharmacodynamic properties of the product. Not only short term but also long-term safety data should be provided. An appropriate risk management plan should be established for agents accumulating in the organism (e.g. deposits of gadolinium in bones and skin). As well as risk(s) related to the agent itself (e.g. immunogenicity, allergic reactions), risks related to the potential for incorrect diagnosis following its use should be taken into consideration while assessing benefit/risk balance of the contrast agent.